Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury

Abstract

Toll‐like receptor (TLR) activation in macrophages plays a critical role in the pathogenesis of acute lung injury (ALI). While TLR inhibition is a promising strategy to control the overwhelming inflammation in ALI, there still lacks effective TLR inhibitors for clinical uses to date. A unique class of peptide‐coated gold nanoparticles (GNPs) is previously discovered, which effectively inhibited TLR signaling and protected mice from lipopolysaccharide (LPS)‐induced ALI. To fast translate such a discovery into potential clinical applicable nanotherapeutics, herein an elegant strategy of “nano‐enabled drug repurposing” with “nano‐targeting” is introduced to empower the existing drugs for new uses. Combining transcriptome sequencing with Connectivity Map analysis, it is identified that the proton pump inhibitors (PPIs) share similar mechanisms of action to the discovered GNP‐based TLR inhibitor. It is confirmed that PPIs (including omeprazole) do inhibit endosomal TLR signaling and inflammatory responses in macrophages and human peripheral blood mononuclear cells, and exhibits anti‐inflammatory activity in an LPS‐induced ALI mouse model. The omeprazole is then formulated into a nanoform with liposomes to enhance its macrophage targeting ability and the therapeutic efficacy in vivo. This research provides a new translational strategy of nano‐enabled drug repurposing to translate bioactive nanoparticles into clinically used drugs and targeted nano‐therapeutics for ALI.

Pharmacologic therapies of ARDS: From natural herb to nanomedicine

“…A recent study showed that inter-lamellar cross-linked multilamellar liposomal vesicles (ICMV) loaded with sivelestat (ICMV-sivelestat) were more readily taken up by neutrophils than with sivelestat alone, effectively inhibited the formation of nets, reduced the production of proinflammatory cytokines, and obviously alleviated lung injury ( Okeke et al, 2020 ). Furthermore, NLC-loaded drugs such as omeprazole ( Sun et al, 2022 ), EUK-134 (a superoxide dismutase/catalase mimetic) ( Howard et al, 2014 ), and MJ-33 (a nitroxide inhibitor) ( Xu et al, 2012 ) have all shown promising anti-inflammatory, antioxidant, and lung-protective effects in a murine model of LPS-induced ALI.…”

Loss of FUT8 in renal tubules ameliorates ischemia‐reperfusion injury‐induced renal interstitial inflammation transition to fibrosis via the TLR3–NF‐κB pathway

“…[27][28][29][30][31] The classic NF-κB pathway upstream regulators TLRs are primary sensors in mediating the inflammatory response and subsequent ligand recognition. TLRs represent an essential component in initiating the acute inflammatory response, [32][33][34][35][36][37] suggesting a critical contribution to IRI and renal fibrosis induction. We determined that CF modifies TLRs.…”

A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway

“…Although inflammation can defend against invading pathogens, it is also a double-edged sword. Usually, deregulated or severe inflammation induced by PAMPs has been linked to tissue injury and inflammatory diseases, such as acute lung inflammatory injury, septic peritonitis, and multiple sclerosis ( Zheng et al, 2019 ; Sun et al, 2022 ). Moreover, some endogenous molecules called damage-associated molecular patterns (DAMPs) could be passively released from the damaged cells of tissue injury ( Zhou et al, 2021 ).…”